The Effectiveness and Value of Rivaroxaban and Icosapent Ethyl as Additive Therapies for Cardiovascular Disease

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England St...

The primary source of evidence for our evaluation of icosapent ethyl was the phase 3, randomized, placebo-controlled REDUCE-IT trial in patients with established CVD or with diabetes and additional risk factors; eligible patients were on a stable dose of statins. 7 Icosapent ethyl reduced the risk of a composite primary endpoint of cardiovascular death, stroke, MI, coronary revascularization, or unstable angina by 25% (HR = 0.75; 95% CI = 0.68-0.83); the trial's key secondary endpoint, cardiovascular death, stroke, or MI, also occurred in fewer patients treated with icosapent ethyl. 7 Treatmentemergent adverse events that occurred with greater frequency in the icosapent ethyl group included peripheral edema, constipation, and atrial fibrillation.
Full details from ICER's review are available in the final evidence report at https://icer-review.org/wp-content / upload s / 2019/02 / IC E R _ C V D_ Fi n a l _ Ev idence _ Report_101719.pdf. 8

Limitations of the Clinical Evidence
The COMPASS trial of rivaroxaban recruited patients with a high risk of recurrent cardiovascular events, but low bleeding risk. In addition, clinical benefits observed in the trial may be somewhat overstated due to early termination of the trial for benefit after a mean follow-up of 23 months.
Results of the REDUCE-IT trial of icosapent ethyl stand apart from many previous studies of omega-3 preparations that showed little to no cardiovascular benefit. Several hypotheses have been posited, including the use of a highly purified EPAonly formulation and the use of a higher daily dose (4 grams/day) than previously studied. It remains unclear, however, whether the results of REDUCE-IT would be reproduced in a confirmatory trial and whether the cardioprotective effects of icosapent ethyl are achievable with alternative omega-3 preparations.
Biomarker changes in the REDUCE-IT trial suggest that the mineral oil-containing placebo may not have been biologically inert; patients in the placebo arm experienced increases in low-density lipoprotein and high-sensitivity C-reactive protein.
These changes raise the possibility that the true effect of icosapent ethyl may be attenuated from that observed in the trial. In addition, it is uncertain whether icosapent ethyl would be effective in patients who are not on statin therapy.

The Effectiveness and Value of Rivaroxaban and Icosapent
Ethyl as Additive Therapies for Cardiovascular Disease

Limitations of the Cost-Effectiveness Model
The results of our analysis were relatively robust to sensitivity and scenario analyses. However, given that the model relied on randomized controlled trial estimates of clinical benefit and harm, the findings should be interpreted with caution when estimating whether these interventions would achieve similar value for money in actual practice.

■■ Policy Discussion
The Midwest Comparative Effectiveness Public Advisory Council (CEPAC; https://icer-review.org/programs/midwestcepac/) is an independent appraisal committee convened by ICER to engage in the public deliberation of the evidence on clinical effectiveness and cost-effectiveness of health care interventions. CEPAC is composed of medical evidence experts and leaders in patient advocacy. Their deliberation includes input from clinical experts and patient representatives specific to the condition under review, as well as formal comment from the public. A policy roundtable concludes each meeting during which representatives from insurers and manufacturers join with clinical experts and patient representatives to discuss how best to apply the findings of the evidence to clinical practice, insurance coverage, and pricing negotiations. The ICER report on additive therapies for CVD was the subject of a CEPAC meeting in September 2019. Following discussion, the CEPAC panel voted 10-1 that the evidence was adequate to demonstrate that the net health benefit provided by rivaroxaban plus ASA is superior to that provided by ASA alone. For the comparison of rivaroxaban plus ASA to DAPT, the panel unanimously voted that there was not adequate evidence to demonstrate that rivaroxaban provided a superior net health benefit. The panel voted 9-2 that the net health benefit provided by icosapent ethyl plus optimal medical management (including statins) is superior to that provided by optimal medical management alone.
The CEPAC panel also voted on "potential other benefits" and "contextual considerations" of both therapies as part of a process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money that are not adequately captured

Long-Term Cost-Effectiveness
We developed a Markov model to compare the cost-effectiveness of rivaroxaban plus ASA with ASA alone and to compare the addition of icosapent ethyl to optimal medical management (including statins) to optimal medical management alone. Both therapies were modeled separately using the same model structure but with distinct populations and model inputs. The model estimated patient survival, quality-adjusted survival, and health care costs over a lifetime time horizon for each intervention and comparator. The base-case analysis used a U.S. health care system perspective with a 3% annual discount rate for costs and health outcomes.
Modeled populations began treatment and could stay in that state or pass into event states of MI, stroke, or death. Those who experienced a cardiovascular event moved into postevent health states, where they could remain or transition to another cardiovascular event state. The model tracked all patients until death. All patients could transition to death from any of the health states, and death could result from all-cause or cardiovascular-related causes.
Results from our model showed that at the estimated annual net prices of $2,215 and $1,625 for rivaroxaban and icosapent ethyl, respectively, incremental cost-effectiveness ratios were $36,000 per quality-adjusted life-year (QALY) for rivaroxaban in comparison with ASA alone and $18,000 per QALY for icosapent ethyl versus medical management alone; additional results (incremental cost per life-year and per equal value lifeyears gained) are presented in Table 1. 9 The results were relatively robust to sensitivity and scenario analyses. In probabilistic sensitivity analyses, 100% of model iterations resulted in an additional cost-per-QALY result below a threshold of $100,000 per QALY gained for both therapies.
ICER's potential budget impact analysis suggested that only approximately 5% of eligible patients with CVD could be treated with either drug before passing a budget impact threshold of $819 million per year over 5 years. Full details on ICER's analyses of cost-effectiveness and potential budget impact, including sensitivity and scenario analyses, are available in the final evidence report on the ICER website. 8

Perspectives on Value
in the analyses of clinical effectiveness and cost-effectiveness. The results of these votes are shown in Table 2 and highlight several factors that the CEPAC panel felt were important for judgments of value. The culminating vote of the CEPAC panel, intended to integrate the elements of the value assessment framework, is normally on the "long-term value for money." As described in ICER's 2017-2019 value assessment framework, questions on long-term value for money are subject to a value vote when incremental cost-effectiveness ratios for the interventions of interest are between $50,000 and $175,000 per QALY in the "base case" analysis. The base case estimates of the cost per QALY for rivaroxaban and icosapent ethyl fell below the lower end of this range; therefore, they were deemed "high long-term value for money" without a vote. There was no value vote taken for the comparison of rivaroxaban plus ASA to DAPT because the evidence was considered inadequate during the clinical vote.
The policy roundtable discussion explored how best to translate the evidence and additional considerations into clinical practice and into pricing and insurance coverage policies.
The full set of recommendations can be found in the final evidence report. Key policy recommendations are as follows: • DAPT should not be considered in a step therapy protocol as a first step before receiving coverage for rivaroxaban. • A decision tool should be developed to help determine appropriate additive therapies for an individual patient. • The U.S. Food and Drug Administration, manufacturers, and the clinical research community should standardize key outcome definitions such as major bleeding.
As noted, ICER's potential budget impact analysis suggested that only approximately 5% of eligible patients with CVD could be treated with either drug before passing a budget impact threshold of $819 million per year over 5 years. During the policy discussion, clinical experts stated that they would consider using rivaroxaban in approximately 30% of eligible patients and icosapent ethyl in the majority of eligible patients. ICER therefore issued an "Access and Affordability Alert" in its final report to signal to policymakers that special measures may need to be considered to ensure that the health care system can absorb the added costs from these therapies over the short  The Effectiveness and Value of Rivaroxaban and Icosapent Ethyl as Additive Therapies for Cardiovascular Disease term without reducing access inappropriately or contributing to rapid growth in health care insurance costs.

■■ Conclusions
Tremendous health gains have been achieved with inexpensive treatments such as aspirin and statins, but high-risk patients continue to be at substantial risk of cardiovascular events even on these treatments. ICER's evidence review suggests that rivaroxaban and icosapent ethyl can provide additional benefits at costs that fall within commonly cited cost-effectiveness thresholds. Nevertheless, the eligible population sizes for both therapies are large, and sustainable access to high-value care for all patients will require thoughtful approaches to managing short-term access and affordability.